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Lesley J Scott
Azacitidine (Vidaza(®)) is a pyrimidine nucleoside analogue of cytidine and is approved in the EU for use in patients with higher-risk myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML), including older patients (aged ≥65 years) with AML with >30 % bone marrow blasts (BMB) who are ineligible for haematopoietic stem cell transplant. This article reviews the clinical efficacy and tolerability of azacitidine in the treatment of these patient populations, as well as summarizing its pharmacological properties...
May 2016: Drugs
Matthew P Burke, Kayla M Borland, Vladislav A Litosh
Nucleoside and nucleobase antimetabolites have substantially impacted treatment of cancer and infections. Their close resemblance to natural analogs gives them the power to interfere with a variety of intracellular targets, which on one hand gives them high potency, but on the other hand incurs severe side effects, especially of the chemotherapeutics used against malignancies. Therefore, the development of novel nucleoside analogs with widened therapeutic windows represents an attractive target to synthetic organic and medicinal chemists...
2016: Current Topics in Medicinal Chemistry
Maria Teresa Voso, Francesco Lo-Coco, Luana Fianchi
PURPOSE OF REVIEW: This review will discuss issues arising along with the expanding use of hypomethylating treatment (HMT) in the management of acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). RECENT FINDINGS: HMT has been shown to induce responses in MDS and AML, and azacitidine (Vidaza, Celgene) has been shown to prolong survival in higher-risk MDS. Recent studies have supported the idea that disease stability may also be a treatment goal, whereas treatment interruption in responding patients is associated with rapid disease relapse and death...
November 2015: Current Opinion in Oncology
Lauren F Ferruccio, Cindy Murray, Karen W Yee, Diana Incekol, Roy Lee, Emma Paisley, Pamela Ng
The azacitidine (Vidaza®) product monograph indicates that doses greater than 4 ml should be divided equally into two syringes and injected into different sites. Although 2 ml is a more commonly used maximum volume for subcutaneous injections, there is a lack of evidence to support the use of any given maximum volume with azacitidine. Applying the status quo of 2 ml to azacitidine results in patients receiving 3-4 injections per visit. This prospective study evaluated the frequency and type of injection site reactions when the maximum subcutaneous injection volume was increased from 2 to 3 ml per injection site...
August 2016: Journal of Oncology Pharmacy Practice
Thomas Mørch Frøsig
This review is focused on research within three different areas of tumor immunology: discovery of new T-cell epitopes and a new immunological antigen (reported in Paper I and II), elucidation of the immunological effects of treatment with a hypomethylating drug (reported in Paper III) and discovery of new conditional ligands (reported in Paper IV). Many melanoma-associated T-cell epitopes have been described, but 45% of these are restricted to human leukocyte antigen (HLA)-A2, leaving the remaining 36 different HLA molecules with only a few described T-cell epitopes each...
August 2015: Danish Medical Journal
Régis T Costello, Amélie Leclercq, Thérèse Le Treut, Carole Sanchez, Delphine Mercier, Gérard Sébahoun
Epigenetic drugs modify DNA methylation and are used in refractory anemia with excess of blasts (RAEB). These drugs may reactivate anti-oncogene expression and restore a normal phenotype instead of inducing antitumor toxicity, although they also have immunosuppressive effects on T-lymphocytes [1] In RAEB and acute myeloid leukemia, a defect in natural killer (NK) cell cytotoxicity has been shown, which relies on abnormal expression of activating receptors. Previous study has shown that 5-azacytidine impaired mRNA synthesis and induced apoptosis in NK cells [2]...
2015: Leukemia Research Reports
Y Beguin, D Selleslag, S Meers, C Graux, G Bries, D Deeren, I Vrelust, C Ravoet, K Theunissen, V Voelter, H Potier, F Trullemans, L Noens, P Mineur
OBJECTIVES: We evaluated azacitidine (Vidaza(®)) safety and efficacy in patients with myelodysplastic syndrome (MDS), acute myeloid leukaemia (AML), and chronic myelomonocytic leukaemia (CMML), in a real-life setting. Treatment response, dose, and schedule were assessed. METHODS: This non-interventional, post-marketing survey included 49/50 patients receiving azacitidine at 14 Belgian haematology centres from 2010-2012. Treatment-emergent adverse events (TEAEs), including treatment-related TEAEs, and serious TEAEs (TESAEs) were recorded throughout the study...
February 2015: Acta Clinica Belgica
David Cheishvili, Lisa Boureau, Moshe Szyf
One of the hallmarks of cancer is aberrant DNA methylation, which is associated with abnormal gene expression. Both hypermethylation and silencing of tumour suppressor genes as well as hypomethylation and activation of prometastatic genes are characteristic of cancer cells. As DNA methylation is reversible, DNA methylation inhibitors were tested as anticancer drugs with the idea that such agents would demethylate and reactivate tumour suppressor genes. Two cytosine analogues, 5-azacytidine (Vidaza) and 5-aza-2'-deoxycytidine, were approved by the Food and Drug Administration as antitumour agents in 2004 and 2006 respectively...
June 2015: British Journal of Pharmacology
Björn Hackanson, Michael Daskalakis
Besides 5-azacytidine (azacitidine, Vidaza®), 5-aza-2'-deoxycytidine (decitabine, Dacogen®) is the most widely used inhibitor of DNA methylation, which triggers demethylation leading to consecutive reactivation of epigenetically silenced tumor suppressor genes in vitro and in vivo. Although antileukemic activity of decitabine is known for almost 40 years, its therapeutic potential in hematologic malignancies has only recently led to its approval in higher-risk MDS patients and as first-line treatment in AML patients>65 years who are not candidates for intensive chemotherapy...
2014: Recent Results in Cancer Research
Carmen S Tellez, Marcie J Grimes, Maria A Picchi, Yushi Liu, Thomas H March, Matthew D Reed, Aram Oganesian, Pietro Taverna, Steven A Belinsky
The DNA methyltransferase (DNMT) inhibitor vidaza (5-Azacytidine) in combination with the histone deacetylase inhibitor entinostat has shown promise in treating lung cancer and this has been replicated in our orthotopic lung cancer model. However, the effectiveness of DNMT inhibitors against solid tumors is likely impacted by their limited stability and rapid inactivation by cytidine deaminase (CDA) in the liver. These studies were initiated to test the efficacy of SGI-110, a dinucleotide containing decitabine that is resistant to deamination by CDA, as a single agent and in combination with entinostat...
November 1, 2014: International Journal of Cancer. Journal International du Cancer
Robert M Campbell, Peter J Tummino
Over the past several years, there has been rapidly expanding evidence of epigenetic dysregulation in cancer, in which histone and DNA modification play a critical role in tumor growth and survival. These findings have gained the attention of the drug discovery and development community, and offer the potential for a second generation of cancer epigenetic agents for patients following the approved "first generation" of DNA methylation (e.g., Dacogen, Vidaza) and broad-spectrum HDAC inhibitors (e.g., Vorinostat, Romidepsin)...
January 2014: Journal of Clinical Investigation
Richard L Momparler
5-Aza-2'-deoxycytidine (5-AZA-CdR, decitabine, Dacogen®) and 5-azacytidine (5-AC, Vidaza®) are epigenetic agents that have been approved for the clinical treatment of the hematological malignancy myelodysplastic syndrome (MDS) and are currently under clinical evaluation for the treatment of acute myeloid leukemia (AML). Most investigators currently classify 5-AZA-CdR and 5-AC as inhibitors of DNA methylation, which can reactivate tumor suppressor genes silenced by this epigenetic event. Examination of the pharmacology of these analogues reveals important differences with respect to their molecular mechanism of action...
2012: Pharmaceuticals
Drorit G Merkel, Arnon Nagler
Modern treatment of myelodysplastic syndromes (MDS) with hypomethylating agents (HMAs) such as azacitidine (Vidaza) and decitabine (Dacogen) has changed the clinical landscape of these disorders. Novel drug combinations of HMAs with histone deacetylase inhibitor therapy may synergistically target different dysregulated molecular mechanisms within MDS clones. This article reviews current trial data concerning the use of the main HMAs in MDS patients where intensive chemotherapy and allogeneic stem cell transplantation is generally not an option...
December 2013: Expert Review of Hematology
John Wrangle, Wei Wang, Alexander Koch, Hariharan Easwaran, Helai P Mohammad, Frank Vendetti, Wim Vancriekinge, Timothy Demeyer, Zhengzong Du, Princy Parsana, Kristen Rodgers, Ray-Whay Yen, Cynthia A Zahnow, Janis M Taube, Julie R Brahmer, Scott S Tykodi, Keith Easton, Richard D Carvajal, Peter A Jones, Peter W Laird, Daniel J Weisenberger, Salina Tsai, Rosalyn A Juergens, Suzanne L Topalian, Charles M Rudin, Malcolm V Brock, Drew Pardoll, Stephen B Baylin
Innovative therapies are needed for advanced Non-Small Cell Lung Cancer (NSCLC). We have undertaken a genomics based, hypothesis driving, approach to query an emerging potential that epigenetic therapy may sensitize to immune checkpoint therapy targeting PD-L1/PD-1 interaction. NSCLC cell lines were treated with the DNA hypomethylating agent azacytidine (AZA - Vidaza) and genes and pathways altered were mapped by genome-wide expression and DNA methylation analyses. AZA-induced pathways were analyzed in The Cancer Genome Atlas (TCGA) project by mapping the derived gene signatures in hundreds of lung adeno (LUAD) and squamous cell carcinoma (LUSC) samples...
November 2013: Oncotarget
Jacques Raphael, Alexander Valent, Colette Hanna, Nathalie Auger, Odile Casiraghi, Vincent Ribrag, Stephane De Botton, Veronique Saada
BACKGROUND: Myeloid sarcoma (MS) is a rare extra-medullary tumour of the myeloid lineage, which can be a difficult diagnosis to make. CASE PRESENTATION: We report the case of a 73-year-old male with a right-sided nasopharyngeal mass revealed on CT scan and MRI. RESULTS: An initial cytological and histological examination suggested a high-grade lymphoma. Nevertheless, the final diagnosis was a MS with an unusual involvement of the nasopharynx that was treated with a conventional induction leukemia therapy...
June 2014: Head and Neck Pathology
Flora Chik, Ziv Machnes, Moshe Szyf
DNA-demethylating agents activate tumor suppressor genes that are silenced by DNA methylation in cancer and are therefore emerging as a novel approach to cancer therapy. 5-azacytidine (VIDAZA), the first representative of this class of drugs was approved for treatment of myelodysplastic syndromes and is currently being tested on other cancers including solid tumors. However, 5-azacytidine or its deoxy-analog, 5-aza-2'-deoxycytidine (5-azaCdR) could also induce methylated prometastatic genes by DNA demethylation and induce cancer cell invasiveness...
January 2014: Carcinogenesis
Sascha Venturelli, Alexander Berger, Timo Weiland, Frank Essmann, Michaela Waibel, Tina Nuebling, Sabine Häcker, Martin Schenk, Klaus Schulze-Osthoff, Helmut R Salih, Simone Fulda, Bence Sipos, Ricky W Johnstone, Ulrich M Lauer, Michael Bitzer
Epigenetic alterations are a hallmark of cancer that govern the silencing of genes. Up to now, 5-azacytidine (5-aza-CR, Vidaza) and 5-aza-2'-deoxycytidine (5-aza-dC, Dacogen) are the only clinically approved DNA methyltransferase inhibitors (DNMTi). Current effort tries to exploit DNMTi application beyond acute leukemia or myelodysplastic syndrome, especially to solid tumors. Although both drugs only differ by a minimal structural difference, they trigger distinct molecular mechanisms that are highly relevant for a rational choice of new combination therapies...
October 2013: Molecular Cancer Therapeutics
Massimo Martino, Roberta Fedele, Tiziana Moscato, Francesca Ronco
Aberrant DNA methylation is a key pathological mechanism in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), and provides rationale for the clinical development of hypomethylating agents (HMAs) for the treatment of these diseases. One HMA, azacitidine (Vidaza®, Celgene Corp.), has demonstrated improved survival versus conventional care regimens in patients with intermediate-2/high-risk MDS and AML (20-30% blasts) and has a favorable tolerability profile. Emerging evidence indicates that azacitidine can have an immunomodulatory effect by, for example, increasing functional regulatory T-cell (Treg) numbers and killer-cell-immunoglobulin-like receptor expression...
July 2013: Current Cancer Drug Targets
T Menter, M Schlageter, L Bastian, R Haberthür, A E Rätz Bravo, A Tzankov
Some chemotherapeutic agents can cause iatrogenic lymphoproliferative disorders. In analogy to what has been observed with other nucleoside analogues such as cladribine and fludarabine, we document the first case of an Epstein-Barr virus-positive, iatrogenic immunodeficiency-associated, lymphoproliferative disease, formally resembling polymorphic post-transplant lymphoproliferative disease in a patient treated with azacitidine (Vidaza) for chronic myelomonocytic leukaemia (CMML). A 78-year-old female patient was diagnosed with CMML in January 2012, and treatment with azacitidine was initiated, which lasted for five cycles from February until June 2012...
March 2014: Hematological Oncology
Cindy Murray, Annie Wereley, Shannon Nixon, Carol Hua-Yung, Sarah von Riedemann, Sandra Kurtin
Azacitidine (5-azacytidine, VIDAZA) is a disease-modifying agent that improves survival, reduces transfusion dependence, and reduces progression to acute myeloid leukemia in patients with higher risk myelodysplastic syndromes. Azacitidine injection is associated with characteristic adverse events (AEs) that must be managed in order for patients to stay on therapy and achieve optimal therapeutic outcomes. These AEs include injection-site reactions, cytopenias, and gastrointestinal effects. Oncology nurses are uniquely positioned to provide patient support and counselling, thereby helping patients and their families set clear expectations for azacitidine therapy...
2012: Canadian Oncology Nursing Journal, Revue Canadienne de Nursing Oncologique
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